Methods for imaging pulmonary and cardiac vasculature and evaluating blood flow using dissolved polarized 129Xe

ABSTRACT

MR spectroscopy and imaging method for imaging pulmonary and cardiac vasculature and the cardiac region and evaluating blood flow or circulatory deficits use dissolved phase polarized  129 Xe gas and large flip angle excitation pulses. Pulmonary and cardiac vasculature MRI images are obtained by delivering gas to a patient via inhalation such as with a breath-hold delivery-procedure, exciting the dissolved phase gas with a large flip angle pulse, and generating a corresponding image. Preferably, the image is obtained using multi-echo imaging techniques. Blood flow is quantified using low field MR spectroscopy and an RF excitation pulse with a frequency which corresponds to the resonance of the dissolved phase  129 Xe.

RELATED APPLICATIONS

This application is a 37 CFR § 1.114 continuation of U.S. PatentApplication Ser. No. 09/271,476, filed Mar. 17, 1999, which claims thebenefit of priority from Provisional Application Ser. No. 60/078,384filed Mar. 18, 1998.

GOVERNMENT GRANT INFORMATION

This invention was made with Government support under U.S. Air ForceGrant number F41624-97-C-9001. The United States Government has certainrights in this invention.

FIELD OF THE INVENTION

The present invention relates to magnetic resonance imaging (“MRI”) andMR spectroscopy using hyperpolarized noble gases. More particularly, thepresent invention relates to imaging techniques using dissolved phasenoble gases.

BACKGROUND OF THE INVENTION

Conventionally, MRI has been used to produce images by exciting thenuclei of hydrogen molecules (present in water protons) in the humanbody. However, it has recently been discovered that polarized noblegases can produce improved images of certain areas and regions of thebody which have heretofore produced less than satisfactory images inthis modality. Polarized Helium 3 (“³He”) and Xenon-129 (“¹²⁹Xe”) havebeen found to be particularly suited for this purpose. See U.S. Pat. No.5,545,396 to Albert et al., entitled “Magnetic Resonance Imaging UsingHyperpolarized Noble Gases”, the disclosure of which is herebyincorporated by reference herein as if recited in full herein.

In order to obtain sufficient quantities of the polarized gasesnecessary for imaging, hyperpolarizers are used to produce andaccumulate polarized noble gases. Hyperpolarizers artificially enhancethe polarization of certain noble gas nuclei (such as ¹²⁹Xe or ³He) overthe natural or equilibrium levels, i.e., the Boltzmann polarization.Such an increase is desirable because it enhances and increases theMagnetic Resonance Imaging (“MRI”) signal intensity, thereby potentiallyallowing physicians to obtain better images of many tissues and organsin the body.

Generally stated, in order to produce the hyperpolarized gas, thehyperpolarizer is configured such that the noble gas is blended withoptically pumped alkali metal vapors such as rubidium (“Rb”). Theseoptically pumped metal vapors collide with the nuclei of the noble gasand hyperpolarize the noble gas through a phenomenon known as“spin-exchange”. The “optical pumping” of the alkali metal vapor isproduced by irradiating the alkali-metal vapor with circularly polarizedlight at the wavelength of the first principal resonance for the alkalimetal (e.g., 795 nm for Rb). Generally described, the ground state atomsbecome excited, then subsequently decay back to the ground state. Undera modest magnetic field (10 Gauss), the cycling of atoms between theground and excited states can yield nearly 100% polarization of theatoms in a few microseconds. This polarization is generally carried bythe lone valence electron characteristics of the alkali metal. In thepresence of non-zero nuclear spin noble gases, the alkali-metal vaporatoms can collide with the noble gas atoms in a manner in which thepolarization of the valence electrons is transferred to the noble-gasnuclei through a mutual spin flip “spin-exchange”.

Conventionally, lasers have been used to optically pump the alkalimetals. Various lasers emit light signals over various wavelength bands.In order to improve the optical pumping process for certain types oflasers (particularly those with broader bandwidth emissions), theabsorption or resonance line width of the alkali metal can be broadenedto more closely correspond with the particular laser emission bandwidthof the selected laser. This broadening can be achieved by pressurebroadening, i.e., by using a buffer gas in the optical pumping chamber.Collisions of the alkali metal vapor with a buffer gas can lead to abroadening of the alkali's absorption bandwidth.

For example, it is known that the amount of polarized ¹²⁹Xe which can beproduced per unit time is directly proportional to the light powerabsorbed by the Rb vapor. Thus, polarizing ¹²⁹Xe in large quantitiesgenerally takes a large amount of laser power. When using a diode laserarray, the natural Rb absorption line bandwidth is typically many timesnarrower than the laser emission bandwidth. The Rb absorption range canbe increased by using a buffer gas. Of course, the selection of a buffergas can also undesirably impact the Rb-noble gas spin-exchange bypotentially introducing an angular momentum loss of the alkali metal tothe buffer gas rather than to the noble gas as desired. In any event,after the spin-exchange has been completed, the hyperpolarized gas isseparated from the alkali metal prior to introduction into a patient.

Conventionally, gas-phase imaging has been possible using both ³He and¹²⁹Xe, and has been particularly useful in producing ventilation-drivenimages of the lungs, a region where proton images have produced signalvoids. However, in contrast to gas phase imaging, dissolved phaseimaging has proven to be problematic. Dissolved phase imaging uses thesolubility characteristic of ¹²⁹Xe in blood and lipid rich tissue. Thegas phase is thus absorbed or “dissolved” into surrounding tissue orblood vessels and may allow perfusion imaging of the brain, lung, orother regions. Such images can potentially allow for the performance ofnon-invasive studies of the pulmonary vasculature to detect emboli andother circulatory system problems. Unfortunately, once the polarized gashas been dissolved (such as into the blood vessels), it has provendifficult to generate clinically useful images using the dissolved phasegas. Conventionally, dissolved phase imaging is attempted by performinga gas-based “regular” image and then looking for a spatially shifteddissolved phase image. However, the small flip angles typicallyassociated with the “regular” image excitation pulses generally fail toproduce sufficient detectable signal spectra in the dissolved phase,thus generating relatively inadequate dissolved phase images.

For example, MRI images using gas-space-imaging techniques have beengenerated using hyperpolarized ¹²⁹Xe gas. See Mugler III et al., MRImaging and Spectroscopy Using Hyperpolarized ¹²⁹Xe gas: PreliminaryHuman Results, 37 Magnetic Resonance in Medicine, pp. 809-815 (1997).While good correlation is seen between the gas-space signal in the xenonimages and the gas-space signal void in the proton images, the spectraassociated with the dissolved phase signal components were significantlylower than the gas-phase signal.

In addition, conventional imaging with MRI units generally requiresrelatively large magnetic fields. For example, 1.5 Tesla (“T”) units arecommon. The large magnetic fields can require special housing andshielding within the use site. Further, the MRI units must typicallyshim or control the magnetic field in order to produce magnethomogeneity which is suitable for imaging. As noted above, high fieldstrength magnets generally require special handling and have relativelyhigh operating costs. Unfortunately and disadvantageously, both the highfield strength magnet and the relatively high homogeneity requirementscan increase the unit's cost both to the medical facility andultimately, the consumer.

OBJECTS AND SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention todetect and/or manipulate dissolved-phase ¹²⁹Xe signals in a manner thatyields clinically useful images.

It is another object of the present invention to provide an imagingmethod which can obtain useful images of dissolved ¹²⁹Xe in thepulmonary and/or cardiac vasculature.

It is an additional object of the present invention to provide animaging method which yields useful images of the heart and major cardiacvessels using dissolved polarized ¹²⁹Xe.

It is yet another object of the present invention to provide an imagingmethod which can obtain useful information and/or images of dissolved¹²⁹Xe which does not require high magnetic field strength and/or highmagnetic field homogeneity.

It is a further object of the present invention to be able to obtainreal-time blood flow path information such as local perfusion variationor blood flow abnormality using MR spectroscopy.

It is yet a further object of the present invention to provide animaging method which can be used to determine quantitative measures ofperfusion using dissolved polarized ¹²⁹Xe.

These and other objects are satisfied by the present invention, whichuses large flip angle (such as 90°) RF excitation pulses to excitedissolved phase gas in the pulmonary vasculature and MR data imageacquisition techniques. In particular, a first aspect of the inventionis directed to a method for obtaining MRI images using dissolvedpolarized ¹²⁹Xe. The method includes positioning a patient in an MRIapparatus having a magnetic field associated therewith. Polarized ¹²⁹Xegas is delivered to the pulmonary region of the patient's body.Preferably, the ¹²⁹Xe is inhaled and, due to the relatively highsolubility of ¹²⁹Xe, in a relatively short period of time, the inhaledpolarized ¹²⁹Xe gas enters into the body in the lung air spaces andeither exists in the lung space as a gas and/or a gas which dissolvesinto adjacent vasculature, tissues, spaces, or organs. Thus, thesolubility of polarized ¹²⁹Xe in the body is such that it generates anassociated hyperpolarized gas imaging phase and a hyperpolarizeddissolved imaging phase. A predetermined region (i.e., a region ofinterest) of the patient's body which has a portion of the dissolvedphase polarized gas therein is excited with a large angle (e.g. 90degree) excitation pulse. At least one MRI image associated with thedissolved phase polarized gas is acquired after the excitation pulse. Ina preferred embodiment, a multi-echo pulse sequence is used to generatean MR image. Further preferably, the excitation step is repeated withina predetermined repetition time. It is also preferred that the excitingstep is performed so that the large angle pulse selectively excitessubstantially only the dissolved phase of the ¹²⁹Xe.

Another aspect of the present invention is a method for evaluating(e.g., measuring, determining, quantifying, observing, monitoring,imaging and/or assessing) the blood flow of a patient. A patient orsubject having a pulmonary and cardiac vasculature is positioned in a MR(magnetic resonance) spectroscopy system. Polarized gaseous ¹²⁹Xe isdelivered to the patient or subject. The pulmonary and cardiacvasculature has an associated blood flow path and a portion of thepolarized gaseous ¹²⁹Xe is dissolved into the pulmonary (and/or cardiac)vasculature blood flow path. The blood flow of the subject can beevaluated (to determine, e.g., xenon enhanced perfusion deficits, bloodflow rate, blood volume, or blood flow path blockage) based on thespectroscopic signal of the dissolved ¹²⁹Xe in the pulmonary (and/orcardiac) vasculature (i.e., a portion of the circulatory system's bloodflow path between and including at least portions of the lungs andheart). Preferably the evaluating step includes a measuring step andblood flow path blockage can be detected by comparing the blood flowrates of healthy subjects with the subject's measured flow rate.

An additional aspect of the present invention is directed toward acardiac imaging method. The method includes positioning a subject in anMRI system and delivering polarized ¹²⁹Xe thereto. At least a portion ofthe polarized ¹²⁹Xe is dissolved into the cardiac blood flow path of thesubject. The dissolved polarized ¹²⁹Xe is excited with a large angle RFexcitation pulse and a MR image associated with the excited dissolvedpolarized ¹²⁹Xe is generated. Preferably, the excitation pulse isselectively delivered to a target area along the cardiac blood flow pathand is spatially limited to limit the depolarizing affect on thepolarized gaseous ¹²⁹Xe outside the target region.

Advantageously, unlike imaging the gas-phase ¹²⁹Xe in the lung whereconventionally small flip angles are used to avoid destroying theavailable ¹²⁹Xe magnetization, there is minimal or no penalty for usinga large flip angle excitation of the dissolved phase ¹²⁹Xe because itwill otherwise flow out of the chest region un-imaged. Indeed, a rapidlarge angle (such as 90 degree) pulse imaging sequence makes optimal useof the dissolved magnetization. The excitation repetition rate should befast enough to capture the ¹²⁹Xe before it flows out of the chestregion. Such an imaging method can provide useful two (2) and three (3)dimensional dissolved phase images of the pulmonary and cardiacvasculature, images of anatomical features along the cardiac blood flowpath, and patient blood flow rates and potential defects in thestructure along the blood flow path of interest.

Further advantageously, blood flow abnormalities, perfusion variations(deficits or increases) and blood flow rate evaluation methods inspectroscopic systems according to the instant invention can be used inMRI units with reduced magnetic fields (such as 0.15 Tesla) and lessrestrictive homogeneity requirements. Further, the instant invention canuse spectroscopic or MRI imaging techniques to obtain signal datacorresponding to a quantity of dissolved polarized ¹²⁹Xe before andafter a physiologically active substance is administered to a human oranimal body to evaluate the efficacy of the drug treatment or toquantitatively analyze a subject's blood flow.

The foregoing and other objects and aspects of the present invention areexplained in detail herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of 25 ¹²⁹Xe spectra (one spectrum per second) from thechest of a healthy human volunteer, showing the temporal evolution ofthe gas-phase and dissolved phase signal components during and after a16-second breath-hold period.

FIG. 2 is a schematic diagram of the human body illustrating dissolutionphase imaging according to the method of the present invention.

FIG. 3 is a graphical representation of a large angle radio frequency(“RF”) excitation pulse sequence and exemplary corresponding echosequences according to one of the methods of the present invention.

FIG. 4 is a schematic diagram of the human blood vascular system showingthe dissolved ¹²⁹Xe blood flow path according to one embodiment of amethod according to the present invention.

FIG. 5 is a schematic diagram of the aorta shown of FIG. 4.

FIG. 6 is a flow chart illustrating one embodiment of a method forspectroscopic imaging according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which preferred embodiments ofthe invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein. Like numbers refer to like elementsthroughout. Layers and regions may be exaggerated for clarity.

As known to those of skill in the art, polarized gases are collected,frozen, thawed, and used in MRI applications. For ease of description,the term “frozen polarized gas” means that the polarized gas has beenfrozen into a solid state. The term “liquid polarized gas” means thatthe polarized gas has been or is being liquefied into a liquid state.Thus, although each term includes the word “gas”, this word is used toname and descriptively track the gas which is produced via ahyperpolarizer to obtain a polarized “gas” product. Thus, as usedherein, the term “gas” has been used in certain places to descriptivelyindicate a hyperpolarized noble gas product and may be used withmodifiers such as solid, frozen, dissolved, and liquid to describe thestate or phase of that product. Also, for preferred embodiments, thehyperpolarized gas is processed such that it is non-toxic and suitablefor delivery to a human subject.

Various techniques have been employed to accumulate and capturepolarized gases. For example, U.S. Pat. No. 5,642,625 to Cates et al.,describes a high volume hyperpolarizer for spin polarized noble gas andU.S. Pat. No. 5,809,801 to Cates et al. describes a cryogenicaccumulator for spin-polarized ¹²⁹Xe. Co-pending U.S. application Ser.No. 08/989,604 to Driehuys et al., entitled “Methods of Collecting,Thawing, and Extending the Useful Life of Polarized Gases and AssociatedApparatus”, describes an improved accumulator and collection and thawmethods. The disclosures of these documents are hereby incorporated byreference as if recited in full herein.

As used herein, the terms “hyperpolarize”, “polarize”, and the like,mean to artificially enhance the polarization of certain noble gasnuclei over the natural or equilibrium levels. Such an increase isdesirable because it allows stronger imaging signals corresponding tobetter MRI (and spectroscopy) images of the substance and a targetedarea of the body. As is known by those of skill in the art,hyperpolarization can be induced by spin-exchange with an opticallypumped alkali-metal vapor or alternatively by metastability exchange.See Albert et al., U.S. Pat. No. 5,545,396.

Referring now to the drawings, FIG. 1 illustrates the temporal evolutionof the gas-phase and dissolved-phase signal components during and aftera 16 second patient breath holding period as shown in Mugler III, etal., supra. The data acquisition began immediately after gas inhalation.The dissolved-phase spectra are shown on the left side of the figure.The vertical scale for the dissolved-phase spectra has been enlarged bya factor of ten over that of the gas-phase spectra (on the right side ofthe figure). As shown, peaks at approximately 185, 196, and 216 partsper million (“p.p.m.”) can be seen in the dissolved-phase spectra. Thedissolved phase is thus shifted about 200 p.p.m. of chemical shift alongthe readout direction between the gas phase of xenon. These spectra werecollected using a 10 degree hard RF pulse (so as to equally excite thegas and the dissolved phase components).

Imaging the Pulmonary Vasculature

The method of the instant invention recognizes that FIG. 1 indicatesthat the dissolved phase xenon signal strength appears to track veryclosely with the gas-phase signal strength. Accordingly, the presentinvention further finds that the close tracking of the signal strengthsindicates extremely rapid equilibrium of the ¹²⁹Xe concentration in thepulmonary blood with the ¹²⁹Xe concentration in the lung. In addition,the instant invention recognizes that there is minimal or no build-up ofdissolved ¹²⁹Xe concentration over time. Thus, the instant inventionincorporates the rapid equilibration and lack of magnetization build-upto provide improved imaging methods to obtain clinically usefuldissolved phase ¹²⁹Xe images.

Generally stated, in a preferred embodiment, a patient is positioned inan MRI unit and exposed to a magnetic field. The MRI unit typicallyincludes a super-conducting magnet, gradient coils (with associatedpower supplies), a surface coil (transmit/receive RF coil), and a RFamplifier for generating RF pulses set at predetermined frequencies. For¹²⁹Xe imaging at 1.5T field strength, the MRI unit is set to operate inthe gas-phase at about 17.6 MHz. Preferably, the dissolved phaseexcitation frequency is shifted below the gas phase excitationfrequency. More preferably the dissolved phase excitation is shifted tobe about 200 ppm lower than the gas phase excitation frequency(corresponding to the chemical shift). Thus, in a preferred embodiment,the dissolved phase ¹²⁹Xe RF excitation frequency is about 3.52 kHzlower than the associated gas-phase excitation frequency. In yet anotherpreferred embodiment, the imaging method employs a 17.6 MHz gas phaseexcitation pulse and an associated dissolved phase excitation pulse ofpreferably about 17.59648 MHz. Of course, the magnet field strength andexcitation frequency can vary as is well known to those of skill in theart.

In any event, the RF pulse(s) is transmitted to the patient to excitethe nuclei of the polarized ¹²⁹Xe. The surface coil is tuned to aselected frequency range and positioned adjacent the targeted imagingregion to transmit the excitation pulses and to detect responses to thepulse sequence generated by the MRI unit. Preferred surface coils forstandard chest imaging include a wrap-around coil with conductorspositioned on both the front and back of the chest. Examples ofacceptable coils known to those of skill in the art include a bird cageconfiguration, a Helmholtz pair, a surface coil, and a solenoid coil(for permanent magnets).

The patient inhales a (predetermined) quantity of polarized ¹²⁹Xe gasinto the pulmonary region (i.e., lungs and trachea). Preferably, afterinhalation, the patient holds his or her breath for a predetermined timesuch as 5-20 seconds. This can be described as a “breath-hold” delivery.Examples of suitable “single dose” quantities of polarized gases forbreath-hold delivery include 0.5, 0.75, and 1.0 liters of gas.Preferably, the dose at inhalation contains gas with a polarizationlevel above 5%, and more preferably a polarization level above about20%.

As schematically shown in FIG. 2, subsequent to inhalation, at least aportion of the polarized gas enters into a dissolved state such that itenters the pulmonary vasculature, including the boundary tissue, cells,membranes, and pulmonary blood vessels such as capillaries, venules,veins, and the like. A substantial amount of the dissolved polarized¹²⁹Xe which enters the pulmonary vasculature then ultimately enters theblood stream with an associated perfusion rate and cycles to the heartvia the left atrium, then to the left ventricle and out through theaorta. In the methods according to the instant invention, thedissolved-phase ¹²⁹Xe directly enters the venous side of the pulmonaryvasculature. However, it is believed that information regarding thearterial side of the vasculature can be obtained due to the symmetrybetween the venous and arterial passages. For example, it is believedthat if there were an arterial blockage, the method of the presentinvention can generate an “apparent” venous-side defect whichcorresponds to an “actual” arterial defect.

In overview, according to this preferred method of the instantinvention, shortly after inhalation of a suitable amount ofhyperpolarized ¹²⁹Xe gas (or gas mixture), the MRI unit delivers a largeflip angle RF excitation pulse to a selected portion of the pulmonaryvasculature. As used herein, large flip angle means an angle which isgreater than about 30 degrees. Preferably, the excitation pulse isgreater than about 45 degrees. More preferably, the excitation pulse isgreater than about 75 degrees and most preferably about a 90 degreeexcitation pulse. A 30 degree flip angle will generally yield about 50%as much signal as a 90 degree flip (45 degrees typically giving about70% as much signal).

It is also preferred that the RF excitation is selectively performed.That is, that “selective excitation” is generated such that it excitesonly certain frequencies, i.e., that it excites substantially only thedissolved phase polarized gas. An exemplary delivery of a selectiveexcitation pulse is via a “hard” pulse. As used herein, “hard” pulseincludes pulses where the RF is turned on for a short pulse time(“t_(pulse)”) and then shortly thereafter, indeed preferablysubstantially “instantly”, turned off. However, short pulse times canyield uncertainty in the associated frequency it generates. Therefore,in a preferred embodiment, selective excitation is performed such thatthe pulse frequency is centered on the dissolved gas phase resonancedesired (i.e., 17.59648 MHz) and has a pulse time, tpulse, such that theassociated frequency is below the corresponding gas phase excitationfrequency (i.e., 17.6 MHz). For example, one frequency spectrum of asquare excitation pulse having a time t_(pulse) and which is centered ona frequency (“fo”) can be described by the equation:

 sin(a(f−fo)/a(f−fo)),

where a=3.1416*t_(pulse).

Therefore, the pulse time t_(pulse) is preferably set so that the sin(a(f−fo))=0 for the gas phase component. Stated differently, the pulsetime t_(pulse) is determined according to the relationshipt_(pulse)=1/(f−fo). In one embodiment, for a 1.5 T magnetic fieldstrength, f−fo equals 3.52 kHz and t_(pulse) is about 284 μseconds(10⁻⁶). Of course, as will be recognized by those of skill in the art,alternative approaches can also be used, such as but not limited to,sine pulses, gaussian pulses, and the like.

In a preferred embodiment, the selective excitation is timed such thatit excites the entire pulmonary blood volume. The pulmonary blood volumeincludes the volume of blood which fills the blood passages associatedwith the circulatory system between and/or within the lungs and theheart (which can include the volume of blood or a portion of the volumeof blood within the boundary lung tissue and/or heart). More preferably,in the method of the present invention, the blood volume of interest isestimated as about half the volume between the right ventricle and theleft atrium (because of the expected T₁ of the dissolved phase polarized¹²⁹Xe in the blood, it is likely that only the venous side of thecirculatory system will include ¹²⁹Xe with sufficient polarizationlevels to provide detectable signal strength). Exemplary volumes will bediscussed further below. Advantageously, unlike imaging the gas-phase¹²⁹Xe in the lung where conventionally small flip angles are used toavoid destroying the available magnetization, there is minimal and mostlikely no penalty for using a large flip angle excitation of thedissolved phase ¹²⁹Xe in the pulmonary vasculature because themagnetization will otherwise flow out of the chest region un-imaged.Further, according to the preferred method of the present invention,“fresh” magnetization is substantially continuously flowing in from thecapillary beds during the procedure.

The present invention is preferably employed to evaluate blood flowthroughout the pulmonary and cardiac vasculature and/or to evaluateblood flow in particular localized regions of the pulmonary and cardiacvasculature. The term “pulmonary and cardiac vasculature” as used hereinincludes all of the blood vessels within the lungs and/or heart, thechambers of the heart, the passages between the chambers of the heart,as well as the blood vessels between the lungs and heart, and bloodvessels between the lungs or heart and other tissues and/or organs. Thepulmonary and cardiac vasculature includes, but is not limited to, thepulmonary veins and arteries and associated capillaries, the left andright atria of the heart, the left and right ventricles of the heart,the myocardium, the aorta and aortic arch, the coronary artery, thecoronary arteries, the subclavian arteries, and the carotid arteries.

More preferably, the imaging methods of the present invention arecarried out to provide clinically useful images of the left and rightpulmonary veins and associated capillaries, the left atrium and leftventricle, the myocardium, the ascending aorta, the coronary arteries,the aortic arch, the descending aorta, the left and right subclavianarteries, and the left and right carotid arteries.

Immediately upon inhalation of hyperpolarized ¹²⁹Xe into the lungs, Xebegins to dissolve into the pulmonary blood stream. The concentration ofXe in the pulmonary capillary beds (“[Xe]_(P)”), can be assumed toequilibrate instantaneously with the concentration of Xe in the lung gasspaces (“[Xe]_(L)”), thus the relationship can be stated as:

[Xe] _(P) =λ[Xe] _(L),  (1)

where “λ” is the Xe blood/gas partition coefficient or blood solubility.This concentration can be expected to equilibrate in the venous side ofthe pulmonary vasculature just a few seconds after inhalation as will bediscussed further below. The standard unit for concentration is an“amagat” which refers to 1 atmosphere of gas pressure at a temperatureof 273 K. For humans whose lungs contain one atmosphere of gas and whosetemperature is about 310 K, all gas densities should be scaled down by afactor of about A=0.88 amagat per atmosphere. For a patient inhaling avolume (“V_(Xe)”) of Xe into their lungs of volume (“V_(L)”), theresulting Xe density in the lung [Xe]_(L) will be $\begin{matrix}{\lbrack{Xe}\rbrack_{L} = {A{\frac{V_{Xe}}{V_{L}}.}}} & (2)\end{matrix}$

Thus, the concentration of Xe in the pulmonary blood [Xe]_(P) will berelated to the inhaled gas volume V_(Xe), and can be stated by theexpression: $\begin{matrix}{\lbrack{Xe}\rbrack_{P} = {\lambda \quad A{\frac{V_{Xe}}{V_{L}}.}}} & (3)\end{matrix}$

For reference, an estimate of λ for Xe in blood is that λ≈0.15. Thus, asan example, a patient who inhales 1 L of Xe into his 6 L lung will yielda Xe density in the lungs of [Xe]_(L)≈0.15 amagat, and correspondingly aXe density in the pulmonary capillary beds of [Xe]_(p)≈0.02 amagat.Thus, the dissolved polarized ¹²⁹Xe gas in the pulmonary capillary bedsis approximately ⅙ the concentration of the lung gas.

In operation, upon crossing the gas/blood barrier, the dissolvedpolarized ¹²⁹Xe is transported out of the lung into the heart and thenout to the remainder of the body. However, as noted above and generallystated, once the ¹²⁹Xe has been transported out of the heart, it islikely that it will no longer be useful for pulmonary or cardiacimaging. Therefore, it is preferred that the imaging is performed in amanner which uses the polarization before it is transported out of theheart and dispersed into the body, potentially resulting in a loss ofthe useful pulmonary (and/or cardiac) vasculature magnetization.

The timescale for ¹²⁹Xe transport out of the pulmonary region or chestarea (“t_(p)”) is a function of pulmonary blood flow rate (“Q”) andpulmonary blood volume (“V_(p)”) which can be expressed by thefollowing: $\begin{matrix}{t_{p} = {\frac{V_{p}}{Q}.}} & (4)\end{matrix}$

Thus, to determine t_(p), one can assume that the volume of pulmonaryvenous blood between the lung and the heart (“V_(p)”) is such thatV_(p)≈200 cubic centimeters (“cc”) and that the pulmonary blood flowrate (Q) is approximately Q≈80 cc/s. See R. M. Berne, Physiology(Mosby-Yearbook, Inc., St. Louis, Mo., 3d ed. 1993). With thesenumerical assumptions, the transit time from lung to heart is determinedto be less than 3.0 seconds, and more particularly t_(p)≈2.5 seconds. Ofcourse, as will be understood by those of skill in the art, alternativeblood volumes will yield alternative transit times. For example, anotherconventional source estimates a blood flow of about 5.5 L/min (92cc/sec) and a total blood volume in the pulmonary vessels at any onetime of about 1.0 L (of which 100 ml are in the capillaries). Accordingto one method of the instant invention, the relevant blood volume wouldbe 500 ccs from the lung to the heart and the time from dissolution toentry into the heart is then about 5 seconds. Correspondingly, thetransit time out of the capillaries is then about 0.5 seconds. Thus, theimage sequence will depend on the imaging region or volume of interest.Further, as will be appreciated by those of skill in the art, childrenand smaller adults can have less volume while larger adults can havemore, and the corresponding image times can vary accordingly.

In a preferred imaging method of the instant invention, the delaybetween the large angle (preferably 90 degree) RF excitation pulses ispreferably less than t_(p). As will be discussed below, it may beadvantageous to further shorten this delay time. In any event, for T_(R)less than or equal to the time t_(p), signal strength in the (perfusion)image will be substantially linearly proportional to the inhaled gasvolume and the ¹²⁹Xe polarization level of the inhaled gas.

Accordingly, care should be taken when setting the excitation pulserepetition interval T_(R). This is because the setting of T_(R) willaffect both image SNR and determine, to some extent, which parts of thelung or cardiac vasculature will be visualized. A long T_(R) will resultin ¹²⁹Xe polarization or magnetization that is (uniformly) distributedthroughout the veinous side of the pulmonary vasculature. A very shortT_(R) setting results in imaging Xe substantially in the capillary bedsof the lungs. This is because the large flip angle pulse substantiallydestroys the incoming ¹²⁹Xe polarization or magnetization before itreaches the larger vessels and thus the larger blood vessels would notbe rendered visible. Therefore, if it is desired to emphasize or detectemboli in the smaller capillaries, one can restrict imaging to thesmaller vessels by using short repetition times, and even if the smallvessels cannot be resolved individually, a perfusion-associated defectshould nonetheless be detectable.

As shown in FIG. 3, the excitation pulse repetition time (T_(R)) isassociated with either a single echo or multi-echo pulse acquisitionsequence. For each RF pulse, a multi-echo data acquisition is preferablyperformed such that there are at least four received echoes between eachexcitation pulse. Preferably, for a breath-hold delivery of 10 seconds,four RF dissolved phase excitation pulses (about 2.5 seconds apart) aregenerated. Further preferably, for each RF pulse, at least 32corresponding echoes are generated. Further, because increasing numbersof echoes will allow increased amounts of signal to be extracted fromthe dissolved gas. Thus, for example, for a 10 second breath-holddelivery and a T_(R) of 2.5 seconds, for 128 echoes collected for eachRF excitation, the SNR can be improved by a factor of 2 over the 32 echopulse embodiment described above.

The repetition time T_(R) of FIG. 3 is preferably 0.01-3.0 seconds. Inone embodiment, for single echoes, the repetition time betweenexcitation pulses is set at 78 ms or less as will be discussed furtherbelow. More preferably, the repetition time is set such that itcorresponds to the time it takes for a given volume of blood to movefrom the lungs to the heart (“t_(p)”), estimated as stated above atunder 3.0 seconds and preferably at about 2.5 seconds. Further, therepetition time can be adjusted to image specific portions of thepulmonary region. For example, the repetition time can be decreased toemphasize a signal from capillaries in the pulmonary region. Incontrast, the repetition time can be increased to emphasize vasculaturewhich is a further distance from the pulmonary region.

Unlike imaging the gas-phase of the polarized ¹²⁹Xe in the lung, whereconventionally small flip angles are used to avoid destroying theavailable magnetization, there is minimal or no penalty for using alarge flip angle excitation of the dissolved phase polarized ¹²⁹Xebecause it will otherwise flow out of the chest region un-imaged.Indeed, a rapid 90 degree pulse imaging sequence makes optimal use ofthe dissolved ¹²⁹Xe polarization or magnetization. The excitationrepetition rate should be fast enough to capture the ¹²⁹Xe before itflows out of the chest region. Such an imaging method can provide two(2) and three (3) dimensional dissolved phase images of the pulmonaryvasculature.

In a preferred embodiment, an entire perfusion image (MR image directedto the dissolved phase polarized gas) is generated in a singlebreath-hold period (“T_(B)”). For example, one can use a slice-selectiveimage in which the chest is divided into a number of slices (“N_(s)”). Atypical MR image slice comprises a number of phase encode steps(“N_(pe)”) and a number of frequency encode steps (“N_(fe)”). Typicalnumbers of these steps are N_(pe)=128 and N_(fe)=128 (or 256). Forsingle echoes derived from each excitation, 128 separate RF excitationscan be used to generate a single image. Single echoes may be preferredwhere there are relatively short T₂* periods (dissolved phase transverserelaxation times) or adverse blood flow effects.

The number of RF pulses (“N_(rf)”) which can be generated in a singlebreath-hold time is related to repetition time (T_(R)) and breath-holdtime (T_(B)), and can be expressed by: $\begin{matrix}{N_{rf} = {\frac{T_{B}}{T_{R}}.}} & (5)\end{matrix}$

Accordingly, for illustrative purposes, for single-echo imaging with abreath-hold period T_(B)=10 s, then the repetition time is preferablyset such that T_(R)≦78 ms for a single image slice.

In view of the foregoing, the signal strength expected in a given imagevoxel can be analyzed as a function of the image parameters. Theeffective pulmonary volume imaged (“V_(eff)”) can be determined by bloodflow rate (Q) and pulse repetition time (T_(R)), expressed by thefollowing: $\begin{matrix}{V_{eff} = {T_{R}{Q.}}} & (6)\end{matrix}$

To calculate the polarization or magnetization in a given pulmonaryvoxel (“V_(iP)”) one can divide the effective pulmonary image volume(V_(eff)) by the image matrix size, as expressed by equation (7).$\begin{matrix}{V_{iP} = \frac{T_{R}Q}{N_{s}N_{pe}N_{fe}}} & (7)\end{matrix}$

The total signal in each pulmonary vasculature voxel (“S_(iP)”) isproportional to the product of coil gain (“G”), ¹²⁹Xe polarization(“P_(Xe)”), the concentration or density of ¹²⁹Xe in the vasculature([Xe]_(P)), voxel volume (“V_(iP)”), and the sine of the excitationangle used in the pulmonary vasculature (“sin α_(P)”). Thus, therelationship can be expressed as follows: $\begin{matrix}{S_{iP} = {\frac{{GP}_{Xe}{\lambda \lbrack{Xe}\rbrack}_{L}T_{R}Q\quad \sin \quad \alpha_{P}}{N_{s}N_{pe}N_{fe}}.}} & (8)\end{matrix}$

Similarly, the signal strength per voxel of ¹²⁹Xe in the lung (“S_(iL)”)can be stated by equation (9) (the expression “sin α_(L)” representingthe excitation angle used in the lung). $\begin{matrix}{S_{iL} = \frac{{{GP}_{Xe}\lbrack{Xe}\rbrack}_{L}V_{L}\sin \quad \alpha_{L}}{N_{s}N_{pe}N_{fe}}} & (9)\end{matrix}$

Comparing the signal strength in equations (8) and (9) gives a ratio ofsignal strengths per voxel of dissolved versus gaseous polarized ¹²⁹Xeas stated in equation (10). $\begin{matrix}{\frac{S_{iP}}{S_{iL}} = {\frac{\lambda \quad T_{R}Q\quad \sin \quad \alpha_{P}}{V_{L}\sin \quad \alpha_{L}}.}} & (10)\end{matrix}$

As an example, for 128 phase encoding steps, the gas phase image can bemade with α_(L)=7° and the perfusion image with α_(P)=90°. Thus, in thisexample, for T_(R)=78 ms, as calculated above for single-echo imaging,then the relative signal strengths can be estimated as follows:$\begin{matrix}{\frac{S_{iP}}{S_{iL}} = {\frac{{.15} \times {.078}s\quad \times 80\quad {cm}^{3}s^{- 1}}{6000\quad {cm}^{3} \times 0.12} \approx {1 \times {10^{- 3}.}}}} & (11)\end{matrix}$

While the signal strength per voxel is dramatically lower in thedissolved phase than in the gas phase, this lower signal strength doesnot prevent clinically useful perfusion imaging according to the instantinvention as described herein.

Additionally, steps can be taken to increase the signal per voxel forthe perfusion imaging of the pulmonary vasculature as described above.First, one may choose to decrease image resolution to increase signalstrength. In one embodiment, for example, one may choose not to performslice-selective imaging. A full projection image of the chest reducesthe number of image slices (“N_(s)”) to N_(s)=1 from N_(s)=16 forslice-selective imaging with 1 cm thick slices. Further, thefrequency-encode steps (N_(fe)) combined with the non-slice selectiveimaging yields a factor of 32 SNR increase per voxel in the perfusionimage.

A reduction in the number of phase encode steps has two beneficialeffects on image SNR. First, a reduction by 2 of N_(pe) gives a factorof 2 increase in voxel SNR akin to reducing N_(fe). Furthermore, in thesingle-echo imaging discussed so far, a reduction in N_(p) implies acorresponding reduction in the number of RF excitations required N_(rf).This allows us to increase the repetition time T_(R), which allows moretime for magnetization to flow from the lung into the pulmonaryvasculature. Accordingly, reducing N_(pe) by 2 provides another factorof 4 in SNR per voxel, bringing the total signal gain per voxel to 128.Thus, with some resolution sacrifice, signal strengths per voxel of¹²⁹Xe in the pulmonary vasculature can be about 8%-10% or more of thecorresponding voxel signal strength in the lung (i.e., S_(iP)≈0.1S_(iL)).

The image matrix of Mugler III et al. was 64×128×11 for a gas phaseimage of the lung. The voxel SNR was 32 for this image. Given this dataand the steps suggested above, a dissolved phase image of the pulmonaryvasculature, using single-echo 90° excitations spaced 78 ms apart can bemade with a matrix size of 64×64×1 with an SNR of 1.6 in each voxel.Further, as described in co-pending application to Driehuys et al.,“Methods of Collecting, Thawing, and Extending the Useful Life ofPolarized Gases and Associated Apparatus”, (incorporated by referencehereinabove), reliable ¹²⁹Xe polarizations of well above 10% are nowachievable. This is in comparison to the 2% polarization level describedin the Mugler III et al. disclosure. In addition, various surface coilimprovements such as tuning, configuring the coil to have close physicalalignment with the body volume of interest, new coil technology known tothose of skill in the art as circular polarization (“CP”), and the like,can yield another factor of 22 improvement. Thus, and advantageously,this permits an increase in SNR (an improvement of about 30 ispossible), indicating that a pulmonary image of the stated matrix size(64×64×1) can be made with a voxel SNR of about 45.

Signal to noise ratio (“SNR”) improvements in the images can be obtainedby using one or more of thick slices (no slice select), reduced imagematrix size, multi-echo imaging, and signal averaging. In addition, whenmultiple echoes (N_(e)) are used, the number of RF excitation pulses canbe decreased. Further, alternative imaging strategies can be used. Forexample, for multiple echoes (1) T_(R) can be kept constant and moreimages can be generated (multi-slice, dynamic imaging, etc.) (2) T_(R)can be lengthened and thus more area of the vasculature can be imaged,and (3) T_(R) can be kept constant and the multiple echoes can be usedto average lines in k-space to increase the image SNR. For example, iffour echoes are made from each excitation, the same line in k-space canbe imaged four times on each excitation and thereby advantageouslyincrease the image SNR by 2.

As noted above, further signal gains can be obtained if multi-echoimaging strategies are successfully implemented. Therefore, andpreferably, the MRI unit generates subsequent multi-echo imageacquisition, although a single echo imaging is also possible asdescribed above. For ¹²⁹Xe dissolved in blood, it is expected that thetransverse relaxation time (“T₂*”) is relatively long (on the order of100 ms or more). In the absence of undesirable flow effects, one cangenerate multiple echoes within this time. Each echo generated ispreferably a phase-encode step. As an estimate, one can make as many as30 echoes in 100 ms. This number of echoes can allow a large reductionin the number of RF excitations (N_(rf)) and thus further lengthen therepetition time (T_(R)), and increase the SNR per voxel. Preferably, theupper limit for the repetition time of T_(R) is to set it equal to theblood transit time out of the lung t_(p). For T_(R)=T_(p)=2.5 s is setas discussed above, then four RF excitations can be generated during a10 second breath-hold period. In order to generate 128 phase encodesteps, 32 echoes per excitation are used. Therefore, for 32 echoes, theSNR per voxel is increased by a factor of 32 (2500/78=32) over thesingle echo imaging technique described above. That is, the signal gainis linear with echo number, and preferred imaging methods of the instantinvention include multi-echo imaging. With such a signal increase, theprevious estimate suggests that the image matrix size can be increasedto 128×256×10 with a voxel SNR of 8. Thus, multi-echo imaging can allowslice-selective imaging as well.

Preferably, when multi-slice imaging is employed, the slice acquisitionis performed by interleaving the slices. A slice-selective acquisitionwill only excite spins in a given slice of the lung. Once a slice hasbeen excited (and a line of k-space) has been obtained, that slice isnot excited again until the time T_(R) has elapsed and spins (in themagnetized polarized dissolved gas) have flowed back into the slice.However, alternate slices can be excited and imaged during this“waiting” period. Advantageously, such interleaving of slices allowsimage acquisition time to be minimized.

One concern for multi-echo imaging methods is the flow of blood and theaffect on the ability to (re)focus the echoes. Thus, multi-echo imagingmethods may be facilitated by the use of cardiac-gated imaging, and todo all imaging during diastole, the period when blood flow is slowest.In one embodiment, cardiac gating is used to better time/sequence imageacquisition to correspond with the period of slow blood flow in thepatient. Alternatively, other methods of slowing the blood circulationsuch as delivering sedatives or anesthesia to the patient to slow theheart rate may be employed to facilitate multi-echo image acquisition.

As will be appreciated by those of skill in the art, imaging withpolarized dissolved gas depends on transport of sufficient survivingpolarization or magnetization to tissues of interest. In a preferredembodiment, the tissues of interest include the pulmonary region, andparticularly the pulmonary vasculature. As will also be appreciated bythose of skill in the art, polarization decays corresponding to thelongitudinal relaxation time, T1. Dissolved phase ¹²⁹Xe can have arelatively short relaxation time (T1) generally thought to be due to thepresence of oxygen and due to paramagnetic deoxyhemoglobin in the blood.For example, T1 for substantially fully oxygenated human cell membranesis estimated at about 15 seconds. Alternatively, T1 in blood has alsobeen estimated as about 5 seconds. See A. Bifone et al., 93 Proc. Natl.Acad. Sci., p. 12932 (1996). Taking the estimated upper limit of about afive second transit time to the heart as discussed above, the xenonpolarization can be attenuated to about ⅓ of its starting value at theheart. This relationship supports that T_(R) should be shortened to lessthan about 2.5 seconds, and preferably less than about 1-2 seconds.Correspondingly, with about a 2.5 second transit time, the magnetizationcan be calculated as noted above to be about 0.61 of its startingmagnetization.

As is also known to those of skill in the art, the polarized ¹²⁹Xe alsohas an associated transverse relaxation time, T₂. In the dissolvedphase, as noted above, it is estimated that this T₂* is relatively long.Taking advantage of this characteristic, it is preferred that(especially for T₂*'s which are greater than about 100 ms), multi-echoacquisition methods are used. As will be appreciated by those of skillin the art, examples of suitable multi-echo methods include Echo PlanarImaging (“EPI”), Rapid Acquisition with Relaxation Enhancement (“RARE”),FSE (“Fast Spin Echo”), Gradient Recalled Echoes (“GRE”), and BEST.Examples of some suitable pulse sequences can be found in an article byJohn P. Mugler, III, entitled Gradient-Echo MR Imaging, RSNA CategoricalCourse in Physics: The Basic Physics of MR Imaging, 1997; 71-88. Forexample, the article illustrates an example of a standard single RFspin-echo pulse sequence with a 90 degree excitation pulse and a 180degree refocusing pulse. In this diagram, G_(P) is a Phase-encodedgradient, G_(R) is the readout gradient, G_(S) is the section-selectgradient, and RF is the radio frequency. The article also illustrates aGradient Recalled Echo pulse sequence (GRE) with a flip angle α and aRapid Acquisition with Relaxation Enhancement (RARE) pulse sequence aswell as a single shot Echo Planar Imaging (EPI) pulse sequence withgradient recalled echoes.

In summary, according to a preferred embodiment of the pulmonaryvasculature imaging method of the present invention, a single breathinhalation volume “Vxe” of about 0.5-1.25 liters of polarized ¹²⁹Xe isdelivered to a patient for a breath-hold time T_(B) of about 5-15seconds. Longer breath-hold times will allow an increaseddissolved-phase polarized gas perfusion signal to be extracted from thepolarization or magnetization delivered via the lung. In thisembodiment, the large flip angle excitation pulse (“α_(P)”) is about90°. Preferably, the excitation pulse is tailored in frequency andduration to affect only the dissolved ¹²⁹Xe (“selective excitation”),leaving the gas-phase magnetization in the lung substantiallyundisturbed.

Thus, during the breath-hold period, the hyperpolarized ¹²⁹Xe in thelung decays corresponding to the longitudinal relaxation time T1 and theuptake (e.g., absorption, diffusion, or dissolution) of polarized ¹²⁹Xeinto the blood. From generally known oxygen related effects, the gasphase T1 for polarized ¹²⁹Xe in the lungs is estimated at about 35seconds. The decay time constant of magnetization in the lung due toblood uptake is generally described by the equation T_(Q)=V_(L)/(λQ).This equates to about 500 seconds and therefore presents a negligiblepolarization or magnetization decay of the lung gas over the breath-holdperiod. The effective T1 is reduced to about 33 seconds when this effectis included. For T_(B)=10 seconds, the ¹²⁹Xe magnetization in the lung(and the associated dissolved or perfused ¹²⁹Xe magnetization orpolarization) will be reduced according to the equation(e^(−{fraction (10/33)})=0.74) of the starting magnetization value.

In a preferred embodiment, the pulse repetition time T_(R) is selectedfor optimal image contrast where T_(R) is less than or equal to t_(p)(the time it takes for the blood with the dissolved polarized ¹²⁹Xe totravel from the lungs to the heart). As noted above, a shortened T_(R)emphasizes signal from capillary beds while a longer T_(R) can showsubstantially all of the pulmonary vasculature.

As noted above, the dissolved phase imaging can be used toadvantageously detect a pulmonary embolus. As will be appreciated by oneof skill in the art, emboli tend to occur in the arterial side of thepulmonary vasculature, while the ¹²⁹Xe uptake tends to occur on thevenous side of the pulmonary vasculature. However, it is believed thatsymmetry in the venous-arterial branching will allow arterial defects toappear on the venous side. For example, for a patient with a blood clotor obstruction in the left pulmonary artery which occludes substantiallyall blood flow, then the ¹²⁹Xe dissolved phase image will show minimalor no left lung vasculature in the image because there is no flow tocarry the polarized xenon from the capillary beds forward. Similarly, ifthe obstruction or clot is in the first branch of the left pulmonaryartery, the corresponding dissolved phase (“perfusion”) image will notshow a portion of the venous vasculature before the first branching onthe venous side. Further, when imaging to detect emboli, sufficientresolution techniques should be employed to help assure that any embolusin a given arterial vessel is detected. Thus, image resolution should besuch that it corresponds to typical embolism size, vasculature locationand vasculature structure (venous branching).

In a preferred embodiment, due to the approximately 200 p.p.m. chemicalshift between the gas and dissolved phase resonance of the polarized¹²⁹Xe, at least two images including both a perfusion and ventilationimage is generated on a patient during the same imaging session(“differential” imaging). Advantageously, differential images provideadditional image information. For example, the differential image canhelp distinguish between a pulmonary embolus and a matchedventilation/perfusion defect associated with a structural anomaly. Inone embodiment, the inhalation image is generated using polarized ³Hewhile the perfusion image uses polarized ¹²⁹Xe. Preferably, the imagesare generated from two data sets captured on two separate imagingsequences. For images using ¹²⁹Xe as both the inhalation and perfusionmedium, the same breath-hold delivery cycle can be employed for bothsets of image data. In such an embodiment, it is preferred that theperfusion image is generated during the first 10 seconds of thebreath-hold cycle and the remaining gas in the lung is used for aventilation image, i.e., the last five seconds of the delivery cycle. Ofcourse, separate breath-hold delivery cycles can also be used. In anyevent, differential imaging will allow better images with informationwhich correlates the total region (lung space and boundary regions).This should also produce images which detect emboli, perfusion defects,and other circulatory system problems in the pulmonary and/or cardiacvasculature.

Cardiac Imaging Method

Similar to the pulmonary vasculature imaging method described above, theinstant invention also includes cardiac imaging methods using dissolvedhyperpolarized ¹²⁹Xe to image the heart and cardiac blood vessels (inparticular, major cardiac blood vessels). As described above, afterinhalation, the dissolved phase ¹²⁹Xe is transported in the blood flowpath of the pulmonary vasculature to the heart. Subsequent toinhalation, at least a portion of the polarized gas enters into adissolved state which enters the pulmonary vasculature, including theboundary tissue, cells, membranes, and pulmonary blood vessels such ascapillaries, venules, veins, and the like. More specifically, asubstantial amount of the dissolved polarized ¹²⁹Xe ultimately entersthe blood stream with an associated perfusion rate and cycles to theheart via the left atrium, then to the left ventricle and out of theheart. Generally stated, as will be appreciated by those of skill in theart, there is limited or no vascular branching in the blood flow path ofthe heart until after the left ventricle. As such, imaging the left sideof the heart (atrium and ventricle) can be performed with the dissolvedphase polarized ¹²⁹Xe in the associated blood flow path similar to themethods described for imaging the pulmonary vasculature discussed above.Like the pulmonary imaging method, it is preferred that large angleexcitation pulses are generated in a MRI system and that those pulsesare timed in accordance with the blood replenishment rate to the regionof interest.

The inhaled polarized ¹²⁹Xe in the lung gas space acts as asubstantially continuous supply of polarized ¹²⁹Xe for dissolution andentry into the pulmonary blood. Preferably, the large angle pulse“selectively” excites only the blood-dissolved ¹²⁹Xe, leaving the lungwith a sufficient quantity of polarized gas at a sufficient polarizationlevel (i.e., magnetized) and thus available for a substantiallycontinuous supply for the gas to migrate to and enter a dissolved phasein the pulmonary vasculature, and ultimately the associated blood streamduring the imaging procedure. As before, the timing of the RF pulses aredependent on the volume of the region to be imaged (“V”) and the bloodflow rate (Q) as expressed by equation (4). The volume of the leftventricle (V) varies between about 140 ml and 60 ml depending on thephase of the cardiac cycle. The blood flow rate (Q) is estimated asabove (at about 80 cc/s), while T_(p) for the left ventricle isestimated to be above 0.5 and below 2 seconds. More particularly, usingthe above stated parameters, T_(p) is estimated as between about 0.8-1.8seconds; 0.8 s≦t_(p)≦1.8 s. Accordingly, it is preferred that the RFpulse repetition interval T_(R) be set such that it is less than orequal to the corresponding blood flow time t_(p). Of course, any initialpulse should be timed to allow the dissolved ¹²⁹Xe to be transported tothe heart (i.e., 2.5-3.5 seconds after inhalation). Subsequent pulsesare preferably timed to obtain signals from the dissolved polarized gaswhile minimizing the destruction of incoming magnetization. This willallow additional excitation pulses without waiting for the entirevasculature to be refilled with unaffected dissolved polarized gas.

The cardiac imaging method also can be beneficially used to image theheart beyond the left ventricle 5. FIG. 4 shows a section view of theheart 15 with the lungs 25. As shown, the heart 15 includes left andright ventricles 5, 20 and the aorta 8. As also shown, the lungs 25include right and left lungs 10, 15. As illustrated by FIGS. 4 and 5,blood flows from the left ventricle 5 up the ascending aorta 8 a wherethe first branching is to the coronary arteries 9 r, 9 l. Perfusionimaging (dissolved phase polarized ¹²⁹Xe imaging) of these coronaryarteries 9 r, 9 l can provide valuable information about the conditionand status of these arteries, such as blockage, thickening, and thelike. As shown in FIG. 5, continuing along the blood flow path after thecoronary arteries 9 r, 9 l, is the aortic arch 8 b, a quadruplebranching at the top of the arch 8 c (to the right and left carotidarteries and the right and left subclavian arteries) and then thedescending aorta 8 d. As the dissolved ¹²⁹Xe flows along this blood flowpath, the signal is sufficiently strong as to render clinically usefulimages. In summary, the imaging methods of the present invention canrender clinically useful images of target regions which include, but arenot limited to, the left and right pulmonary veins and associatedcapillaries, the left atrium and left ventricle, the myocardium, theascending aorta, the coronary arteries, the aortic arch, the descendingaorta, the left and right subclavian arteries, and the left and rightcarotid arteries. Of course, using polarized gas with increasedpolarization levels (i.e., above 20%) can further expand the dissolvedphase imaging regions.

Further, it is anticipated that perfusion images according to themethods of the instant invention can be used in regions or organs whichabsorb or pass blood such as, the brain, the liver, and the kidney. Inthis application, one can use the methods as described herein,recognizing that some of the polarized dissolved-phase ¹²⁹Xe will beretained in the respective tissues at different chemical shifts.However, as described above, volume calculations of the region or areaof interest can be used to determine the pulse repetition rate tomaximize the use of the dissolved polarization-related signal.

In a preferred embodiment, the method of the present invention uses asmall close-fitting cardiac surface coil to deliver the excitation pulserather than a conventional body coil. This will allow improved SNR andspatially limit the RF pulse to this smaller region, thereby minimizingthe incidental destruction of the ¹²⁹Xe incoming from the pulmonaryvasculature.

In an additional preferred embodiment, the method of the presentinvention uses a pulse and gradient combination which is selective. Thisselection can be slice or volume selective. Conventional imaging methodsare generally “slice” selective. Slice selective images are typicallygenerated by combining a frequency-selective pulse in the presence of az field gradient (“G_(z)”), excitation can be confined to a slice ofthickness “Δz” along the z axis. The z field is defined as the axiswhich extends along the length of the body. The frequency bandwidth ofthe excitation pulse together with the gradient, confines excitation tothe nuclei in the slice, substantially no signals are excited ordetected from areas outside the defined slice.

Volume-selective imaging allow a two-dimensional spatial localizationusing a single pulse. These methods employ RF pulse/gradientcombinations which excite a filled cylinder of spins. In a preferredembodiment, a volume-selective pulse is used, and more preferably, acylindrical imaging volume selection is used. It is believed that thevolume selection is particularly suitable for cardiac perfusion imagesbecause they can advantageously allow coronary artery images while alsominimizing background signal from the left side of the heart. See C. J.Hardy and H. E. Cline, Broadband nuclear magnetic resonance pulses withtwo-dimensional spatial selectivity, J. Appl. Phys., 66(4), Aug. 15,1989; C. J. Hardy et al., Correcting for Nonuniform k-Space Sampling inTwo Dimensional NMR Selective Excitation, 87 Jnl. Magnetic Resonance,639-645 (1990); and Spatial Localization in Two Dimensions Using NMRDesigner Pulses, Jnl. of Magnetic Resonance, 647-654(1989).

A pulse-gradient combination can also limit the collateral damage to theincoming magnetization, thereby maximizing the image SNR. It is alsopreferred that multiple echo signals be used (i.e., multiplegradient-recalled or RF-recalled echoes) to increase image SNR(linearly) with the number of echoes as discussed under the pulmonaryimaging method.

An additional alternative to cardiac imaging is to directly deliverpolarized ¹²⁹Xe to a region of the heart (such as via injection and thelike into the left ventricle muscle) to image the perfusion of theheart. Delivery directly to the right atrium/ventricle can allowperfusion imaging of the return side of the heart. In any event, thepolarized ¹²⁹Xe delivery can be via injection of various phases/vehiclessuch as but not limited to gaseous, dissolved, or liquid phase.Conventional image perfusion methods for this area employ radioactivetracers such as Thalium (“²⁰¹Tl”) or Technetium (“^(99m)Tc”). Usingxenon, which is an inert noble gas, can beneficially replace radioactivetracers which can expose the subject to potentially dangerous elements.

Methods to Evaluate Blood Flow

In addition to the imaging methods described above, the instantinvention also includes MR spectroscopic methods which can be used toevaluate the lung and heart blood flow by using the dissolved-gas phaseof the ¹²⁹Xe inhaled gas which enters the vasculature (lung perfusion)and the blood stream as described above. Generally described, theinstant method is relatively inexpensive and advantageously employs theinhaled hyperpolarized ¹²⁹Xe (as discussed above) to evaluate blood flowin a low-field NMR spectroscopy system. The terms “evaluate” and“evaluating” as used herein are intended to be interpreted broadly andmean that the blood flow of a subject is measured, determined,quantified, observed, monitored, imaged, and/or assessed.

The term “blood flow” as used herein is to be broadly construed. Methodsof evaluating blood flow according to the present invention encompassmethods of determining blood flow rates, perfusion (typically measuredin ml/min/g tissue), comparative blood flow values (monitoring bloodvolume or flow rates as changes over time such as before and after drugtherapy or surgical treatment or real time feed back during surgery toverify success of treatment—without the need for absolute values), bloodvolume, or blood path anomalies, in particular, in the pulmonary and/orcardiac vasculature. Also included in the inventive methods ofevaluating blood flow are methods of determining the presence of absenceof an obstruction to blood flow or local defects in blood passagethrough the vasculature (e.g., from stenosis), in particular, thepulmonary and/or cardiac vasculature.

As described above (such as in Equations 1-6), a patient who inhales 1 Lof Xe into the lungs (having about a 6 L lung volume) will yield aboutor dissolve into about ⅙ of that value of the xenon concentration (0.02amagat) in the pulmonary vasculature and associated blood. In apreferred embodiment, the method uses frequency selective large angle(more preferably 90°) RF excitation pulses which substantially depletesthe ¹²⁹Xe in the pulmonary blood but leaves the hyperpolarized gas inthe lungs substantially undisturbed. In this embodiment, the repetitiontime interval between RF pulses (T_(R)) and the pulmonary blood flowrate (Q) can be used to determine the effective pulmonary volume(V_(eff)) containing (dissolved phase) hyperpolarized ¹²⁹Xe. Seeequation 6, supra. This relationship assumes that T_(R) is less than orsubstantially equal to the time it takes for the polarized ¹²⁹Xe toleave the pulmonary blood (t_(p)). As discussed above, for typical bloodflow rate and estimated volume of venous pulmonary blood, t_(p) isapproximately 2.5 seconds. Thus, with a large RF excitation pulse(preferably, about α=90°), the dissolved pulmonary ¹²⁹Xe signal strengthin the pulmonary blood is proportional to the product of coil gain(“G”), Xe polarization (“P_(xe)”), and polarized Xe density orconcentration in the vasculature ([Xe]_(P)=λ[Xe]_(L)), which can bestated by the following expression:

Sp(T _(R))=GP _(Xe) λ[Xe] _(L) QT _(R)  (12)

Notably, the signal strength is dependent on both the pulse interval(T_(R)) and the blood flow rate (Q). The dissolved signal intensityversus repetition time will have an associated slope which can bemathematically expressed as follows: $\begin{matrix}{\frac{S_{p}}{T_{R}} = {{GP}_{Xe}{\lambda \lbrack{Xe}\rbrack}_{L}Q}} & (13)\end{matrix}$

The slope is directly proportional to the pulmonary blood flow rate (Q).Calibration of the blood flow rate is obtainable by evaluating the gasphase signal (“S_(L)”) in the lung, the signal having an associatedsmall RF tipping angle (excitation angle) (“α_(L)”). The gas phasesignal can be expressed by the equation:

S _(L) =GP _(Xe) [Xe] _(L) V _(L) sin α_(L)  (14)

The pulmonary blood flow rate (Q) can be stated by the ratio of thehyperpolarized ¹²⁹Xe gas and dissolved phase signals. This ratio cancelsreceiver gain (G) and polarization value P_(xe). Accordingly, the bloodflow rate (Q) can be expressed by the following: $\begin{matrix}{Q = \frac{V_{L}\sin \quad {\alpha_{L}\left( {{S_{p}}/{T_{R}}} \right)}}{{\lambda S}_{L}}} & (15)\end{matrix}$

Advantageously, with measurements of the Xe/blood partition coefficient(λ) and the total lung volume (V_(L)), a quantitative measurement ofblood flow is established according to a method of the instantinvention. As will be appreciated by one of skill in the art, lungvolume can be easily established to about 20% accuracy with techniquesknown to those of skill in the art. Preferably, techniques withrelatively improved accuracy such as but not limited to spirometry areused. Accordingly, the instant invention provides a clinically usefulreal-time blood measurement tool.

Further, and advantageously, MR spectroscopy using ¹²⁹Xe can be simplerand less expensive relative to the cost of other MR images. For example,the quantity of polarized gas needed, the polarization level of thepolarized gas, and the isotopic enrichment can be reduced as compared tothose used for conventional polarized gas MR imaging. In one embodiment,the spectroscopic perfusion measurement can be made with about 100 cc ofunenriched gas polarized to only 1-2%. This is in comparison to apolarization of 20% for 500 cc of 80% isotopically enriched ¹²⁹Xe toyield a comparable MR image. Still another advantage is that thespectroscopic methods do not require a polarization calibration becausethe measurement is “self-calibrating”. Stated differently, thepolarization is cancelled by comparing dissolved and gaseous xenonsignal, both of which can be assumed to have identical polarization tothe extent that T1 relaxation in the blood is negligible, which it isfor short T_(R) settings as discussed above. Other advantages includethe use of low magnetic field systems, such as 0.1-1.0 Tesla, andpreferably about 0.075-0.2 T, and more preferably about 0.1-0.15 T. Thelower field limit is established by the length of the pulse needed toget selective excitation. For example, a 200 ppm shift at 1.5 T means afrequency difference of about 3.52 kHz. Thus, for a hard pulse, it isdesired to have a pulse length of about 284 μs so that the gas phaseremains substantially or totally unexcited. Reducing the field by afactor often to 0.15 T gives a frequency difference of 0.352 KHz and thecorresponding discriminating pulse length of about 2.84 ms. Similarly,at 0.015 T (150 G), the pulse length is relatively long (28 ms). Thelonger pulse time at this field strength T2 can potentially degrade thesignal because T2 can dephase the signal before the pulse application iscomplete.

Advantageously, the method can be used successfully in systems havingrelatively poor magnet homogeneity because the field gradients do notadversely impact the spectroscopy perfusion method. By eliminating thenecessity for these items, system operating costs can potentially begreatly reduced.

Further, a simplified and lower cost polarizer system can be used topolarize the ¹²⁹Xe for this method. For example, the low cost polarizersystem can use a lower power optical laser (such as a 10 Watt laser) andreduced accuracy measurement and associated equipment attributed to theelimination of the need for accurate polarization, each of which canprovide additional cost savings over that of other systems used forother imaging methods.

Preferably, the appropriate magnet homogeneity associated with apatient's chest area for the spectroscopy imaging method of the instantinvention is estimated by the corresponding chemical shift of ¹²⁹Xe inthe dissolved phase in the blood over that in the gaseous phase. Thisshift, as discussed above, is about 200 ppm. Thus, in order to achieve“selective” excitation of the dissolved phase, a field homogeneity ofabout 50 ppm or better is preferred. More preferably, a fieldhomogeneity of about 20 ppm or better is used. In contrast, conventionalMRI systems are shimmed to about 1 ppm to operate with about a 1 ppmhomogeneity. The lower limit of the magnetic field strength used in thespectroscopy method of the instant invention can be determined by thepulse time used to selectively excite the dissolved phase (instead ofthe gas phase). The frequency difference (“Δν”) between the gas anddissolved phase can stated by: $\begin{matrix}{{\Delta \quad v} = {\frac{\gamma}{2\pi}\delta \quad {B_{0}.}}} & (16)\end{matrix}$

Wherein B₀ is the strength of the magnetic field, γ is the gyromagneticratio of ¹²⁹Xe and δ is the chemical shift separating the gas anddissolved phases. Accordingly, when applying a pulse which selectivelyexcites one phase rather than the other, the length of the pulse shouldbe sufficiently long to have a sufficiently narrow frequency bandwidth.For example, by Fourier analysis, a square excitation pulse of durationt_(rf) will have an frequency spectrum centered on the pulse frequencywith a frequency width (“Δν_(rf)”) of about 1/t_(rf). Thus, for phasediscrimination, the pulse frequency distribution width is preferablysmaller than the frequency separation between the phases (Δν_(rf)<Δν).Thus, the approximate lower field limit can be written as:$\begin{matrix}{B_{0} \geq {\frac{2\pi}{{\gamma\delta}\quad t_{rf}}.}} & (17)\end{matrix}$

Although the pulse time t_(rf) can be as long as necessary to achievedissolved phase discrimination at the given field strength, the pulselength time is also limited by the timescale of the blood flow effects(t_(p)) as well as T2 and T2*. Preferably, a large number of pulses aregenerated during the time interval (t_(p)). Preferably, at least 25excitation pulses are applied during this interval, more preferably atleast 50, and most preferably about 100 pulses. Assuming the time scaleis about 2.5 seconds, as discussed above, then a preferable pulse time(t_(rf)) is about 25 ms. For γ=7402G⁻¹s⁻¹, an exemplary minimum fieldstrength is about 170 gauss (“G”). This is a relatively low field,approximately {fraction (1/100)} the standard 1.5 T imaging magnet.

In an additional embodiment of the spectroscopic blood flow method ofthe instant invention, pulmonary emboli or other blockage can bedetected by measuring the pulmonary blood flow rate (Q). Thismeasurement is based on normal blood flow rates in healthy subjects.Preferably, the blockage detection method also considers heart rate. Ina preferred embodiment, the detection method correlates the blood flowrate (Q) with heart rate (“R”). For example, the detection methodpreferably uses a normalized flow rate Q/R. Thus, as illustrated by FIG.6, the detection method includes positioning a subject in a MRspectroscopy unit (Block 500) and delivering gaseous polarized ¹²⁹Xe tothe subject (Block 510). A portion of the gaseous ¹²⁹Xe is dissolvedinto the pulmonary vasculature which has an associated perfusion orpulmonary blood flow path (Block 520). The blood flow is evaluated basedon the spectroscopy signal of the dissolved ¹²⁹Xe (Block 530). Thismethod can yield unique real-time information about blood flow andperfusion that is difficult to achieve by other means. In a preferredembodiment, the dissolved phase ¹²⁹Xe is (selectively) excited with alarge flip angle excitation pulse as described above (Block 525). It isalso preferred that the pulse sequence be correlated with the bloodvolume (or flow rate) to maximize the signal with the magnetization inthe blood.

Preferably, the method includes detecting blockage in the blood flowpath of the subject based on the results of the measuring step. In oneembodiment, the blood flow rates of healthy subjects are compared to themeasured flow rate to perform the detecting step. In determining ifthere is a problem, the heart rate is taken into account. Accordingly,in a preferred embodiment, the method uses the heart rate of the subjectto normalize the measured blood flow rate.

Advantageously, for repetition times (T_(R)) which are less than t_(p),the signal will be substantially linear with T_(R). In addition, anintegrated signal versus T_(R) will be proportional to blood flow rate(Q). Thus, a substantially calibrated measurement of the blood flow rate(Q) can advantageously be obtained. This can be done relativelyinexpensively with a low field magnet and with low homogeneityrequirements. Advantageously, such a calibration can be performedaccurately and relatively simply.

In another preferred embodiment, a spectroscopic signal associated withthe dissolved-phase ¹²⁹Xe can be derived such that it represents a bloodvolume or blood flow rate. The patient can then be subjected to a drugtherapy or surgery to treat a cardiac or pulmonary vasculature or bloodflow problem. A second signal can then be obtained and a comparative,relative, or percent increase (or decrease) in blood flow can beobtained without requiring an “absolute value” of blood volume. Such acomparative MR spectroscopy evaluation can be done in real-time toindicate during surgery (such as during angioplasty) whether a bloodflow path obstruction has been removed or diminished. Further, such acomparative measurement or evaluation can be used to determine whetherdrug therapy improved a patient's blood flow (by allowing an increasedblood volume or rate (such as due to a less viscous blood or lipidmanagement) and the like.

Additionally, due to the depolarizing effect of oxygen depleted blood ondissolved phase polarized ¹²⁹Xe, MR spectroscopy signal intensity(reduced or increased) can be used to evaluate conditions associatedwith reduced or increased levels of oxygen along the xenon-blood barrieror blood flow path. The deoxyhemoglobin is paramagnetic and has agreater depolarizing effect on the dissolved phase ¹²⁹Xe. The welloxygenated blood or tissue provide longer T1's compared to oxygenstarved blood or tissue. Thus, a stronger spectroscopy signal relates towell oxygenated levels of oxygen in the tissue or blood while a weakeror lower spectroscopic polarization-based signal relates tooxygen-starved, depleted or deprived regions.

OTHER EMBODIMENTS

The present invention has been described above with respect toparticular preferred embodiments. Those skilled in the art, however,will appreciate that the invention can be employed for a broad range ofapplications. Methods for imaging or obtaining information about bloodflow using dissolved hyperpolarized ¹²⁹Xe can be carried out accordingto the present invention using magnetic resonance or spectroscopictechniques known to those skilled in the art. See, e.g., U.S. Pat. No.5,833,947; U.S. Pat. No. 5,522,390; U.S. Pat. No. 5,509,412, U.S. Pat.No. 5,494,655, U.S. Pat. No. 5,352,979; and U.S. Pat. No. 5,190,744. Seealso Hou et al., Optimization of Fast Acquisition Methods forWhole-Brain Relative Cerebral Blood Volume (rCBV) Mapping withSusceptibility Contrast Agents, 9 J. Magnetic Resonance Imaging 233(1999); Simonsen et al., CBF and CBV Measurements by USPIO BolusTracking: Reproducibility and Comparison with Gd-Based Values, 9 J.Magnetic Resonance Imaging 342 (1999); Mugler III et al., MR Imaging andSpectroscopy Using Hyperpolarized ¹²⁹ Xe gas: Preliminary Human Results,37 Magnetic Resonance in Medicine, pp. 809-815 (1997); Belliveau et al.,Functional Cerebral Imaging by Susceptibility-Contrast NMR, 14 MagneticResonance in Medicine 14 538 (1990); Detre et al., Measurement ofRegional Cerebral Blood Flow in Cat Brain Using Intracarotid ² H ₂ O and² H NMR Imaging, 14 Magnetic Resonance in Medicine 389 (1990); Frank etal., Dynamic Dysprosium-DTPA-BMA Enhanced MRI of the Occipital Cortex;Functional Imaging in Visually Impaired Monkeys by PET and MRI(Abstract), Ninth Annual Scientific Meeting and Exhibition of theSociety of Magnetic Resonance In Medicine (Aug. 18-24, 1990); Le Bihan,Magnetic Resonance Imaging of Perfusion, 14 Magnetic Resonance inMedicine 283 (1990); and Rosen et al., Perfusion Imaging by NuclearMagnetic Resonance, 5 Magnetic Resonance Quarterly 263 (1989). Thecontents of these documents are hereby incorporated by reference as ifrecited in full herein.

In particular embodiments, the present invention can be practiced togive a quantitative assessment of blood flow (more preferably,perfusion) as will be appreciated by one of skill in the art. Accordingto this embodiment, signal intensity can be followed over time, and thearea under the resulting curve can be integrated to give a quantitativemeasure of blood flow. Examples of such quantitative relationships weredeveloped for use with radioactive contrast agents with MR imaging andspectroscopy methods may be particularly suitable for dissolved phase¹²⁹Xe analysis of blood vessels. See, generally, Lassen, CerebralTransit of an Intravascular Tracer may Allow Measurement of regionalBlood Volume but not Regional Blood Flow, 4 J. Cereb. Blood Flow andMetab. 633 (1984). However, it will be appreciated by one of skill inthe art, that, unlike the radioactive contrast agents, the polarizedstates of both the gas and the dissolved phase gas (in the body of asubject) are relatively short and “automatically” terminate within thebody within blood within less than about 1-2 minutes (depending on thepolarization level) from the time when the inhalation procedure orgaseous supply is terminated at the lungs. Therefore, after about 1minute, there is typically no “residue” polarized gas to image or togenerate an MR detectable signal to potentially interfere with MR signalevaluations.

Furthermore, the inventive methods may be used for wide range ofdiagnostic and evaluative applications, preferably those related tocardiac, pulmonary or cardiovascular function, as described in moredetail below.

In preferred embodiments, the inventive methods are used to determineperfusion rates (e.g., absolute and/or relative perfusion), and morepreferably to identify and/or assess the severity of abnormal perfusion.In other particular embodiments, temporal variations in blood flow aredetermined, e.g., to assess the effects of a vasocontractory orvasodilatory substance and/or to identify regions of surgically inducedvariations in blood perfusion.

Other applications of the present invention include, but are not limitedto: identification and assessment of the presence or absence and/orseverity of cardiac ischemias and/or infarcts; localization andassessment of thrombi and plaques; determination of “therapeuticwindows” for administering heparin, vasodilators, antihypertensiveagents, calcium antagonists and the like, e.g., in reversible focalischemia; monitoring of other induced vasodilator effects; detection andquantitative evaluation of the severity of ischemias; monitoring thevasodilatory or vasocontractory effects of a physiologically activesubstance; and monitoring surgically induced blood perfusion variations.

The present invention may further be employed for: assessment ofcerebral perfusion in following induced subarachnoid hemorrhage or inconditions marked by brain dysfunction, e.g., in connection with acutesevere symptomatic hyponatremia; evaluation of new therapies, e.g., inthe treatment of cerebral vasospasm (including but not limited to,anti-thrombolytic therapies, calcium channel blockers, anti-inflammatorytherapies, angioplasty, and the like); assessment of the presence orabsence and/or severity of ischemia in large tissue masses; assessmentof the relationship between blood metabolites and cerebral perfusion incerebral ischemia associated with acute liver failure, e.g., for thetreatment of Alzheimer's disease; evaluation of new therapies forstroke, including but not limited to, t-PA, aspirin antiphospholipids,lupus anticoagulants, antiphospholipid antibodies, and the like;evaluation of risk factors for stroke, e.g., serum lipid levels;evaluation of induced brain hypothermia on cerebral perfusion duringneurosurgery, e.g., for stroke; evaluation of the effects of age oncerebral perfusion, e.g., to study lacunar infarcts; and assessment ofnarcotics, e.g., cocaine, amphetamines, ethanol, and the like, on theischemic brain.

The present invention finds use for both veterinary and medicalapplications. The present invention may be advantageously employed fordiagnostic evaluation and/or treatment of subjects, in particular humansubjects, because it may be safer (e.g., less toxic) than other methodsknown in the art (e.g., radioactive methods). In general, the inventivemethods will be more readily accepted because they avoid radioactivityor toxic levels of chemicals or other agents. Subjects according to thepresent invention can be any animal subject, and are preferablymammalian subjects (e.g., humans, canines, felines, bovines, caprines,ovines, equines, rodents, porcines, and/or lagomorphs), and morepreferably are human subjects.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clause are intended tocover the structures described herein as performing the recited functionand not only structural equivalents but also equivalent structures.Therefore, it is to be understood that the foregoing is illustrative ofthe present invention and is not to be construed as limited to thespecific embodiments disclosed, and that modifications to the disclosedembodiments, as well as other embodiments, are intended to be includedwithin the scope of the appended claims. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A method for MRI imaging the pulmonaryand/or cardiac vasculature using dissolved-phase polarized ¹²⁹Xe,comprising the steps of: delivering polarized ¹²⁹Xe gas to apredetermined region of the patient's body, the polarized gas having adissolved imaging phase associated therewith; exciting a predeterminedregion of the patient's body having a portion of the dissolved phasepolarized gas therein with at least one large flip angle RF excitationpulse; acquiring at least one MR image associated with the dissolvedphase polarized gas after said exciting step, wherein said deliveringstep includes having the patient inhale the polarized ¹²⁹Xe gas into thelungs, the polarized ¹²⁹Xe having a gas phase resonance which is higherthan the dissolved-phase resonance, and wherein at least a portion ofthe polarized ¹²⁹Xe gas enters into the pulmonary vasculature in adissolved-phase, and wherein at least a portion of the dissolved-phasepolarized ¹²⁹Xe then enters the blood stream with an associatedperfusion rate wherein a differential MRI image is obtained whichcomprising data associated with the physiology of the lungs of thepatient, the physiology of the vasculature of the patient, blood flow inthe patient, and perfusion in the patient, the data corresponding toboth the ¹²⁹Xe gas and dissolved-gas phase, and wherein saiddifferential image is obtained by exciting the ¹²⁹Xe gas phase with anRF pulse having an excitation pulse frequency which corresponds to theresonance of the gas phase and exciting the dissolved phase with an RFpulse having an excitation frequency which corresponds to the resonanceof the dissolved phase, and wherein the gas phase RF excitation pulse isa small flip angle pulse and the dissolved phase RF excitation pulse isa large flip angle pulse.
 2. A method for MRI imaging the pulmonaryand/or cardiac vasculature using dissolved-phase polarized ¹²⁹Xe,comprising the steps of: delivering polarized ¹²⁹Xe gas to apredetermined region of the patient's body, the polarized gas having adissolved imaging phase associated therewith; exciting a predeterminedregion of the patient's body having a portion of the dissolved phasepolarized gas therein with at least one large flip angle RF excitationpulse; acquiring at least one MR image associated with the dissolvedphase polarized gas after said exciting step, wherein said deliveringstep comprises having the patient inhale the polarized ¹²⁹Xe gas intothe lungs, the polarized ¹²⁹Xe having a gas phase resonance which ishigher than the dissolved-phase resonance, and wherein at least aportion of the polarized ¹²⁹Xe gas enters into the pulmonary vasculaturein a dissolved-phase, and wherein at least a portion of thedissolved-phase polarized ¹²⁹Xe then enters the blood stream with anassociated perfusion rate; and delivering via inhalation a quantity ofpolarized ³He gas, and wherein a MRI differential image is obtainedcomprising data corresponding to the polarized gas ³He in the lungs inaddition to the dissolved phase polarized ¹²⁹Xe.
 3. A method for MRIimaging the pulmonary and/or cardiac vasculature using dissolved-phasepolarized ¹²⁹Xe, comprising the steps of: delivering polarized ¹²⁹Xe gasto a predetermined region of the patient's body, the polarized gashaving a dissolved imaging phase associated therewith; exciting apredetermined region of the patient's body having a portion of thedissolved phase polarized gas therein with at least one large flip angleRF excitation pulse; and acquiring at least one MR image associated withthe dissolved phase polarized gas after said exciting step, wherein saidexciting step is repeated within a predetermined repetition time, thepredetermined repetition time being less than the time it takes for agiven volume of blood to move from the lungs to the heart, wherein saiddelivering step comprises inhalation of the polarized ¹²⁹Xe gas into thelungs, the ¹²⁹Xe having a gas phase resonance which is higher than thedissolved-phase resonance, wherein at least a portion of the polarized¹²⁹Xe gas enters into the pulmonary vasculature in a dissolved-phase,wherein at least a portion of the dissolved-phase polarized ¹²⁹Xe thenenters the blood stream with an associated perfusion rate and whereinsaid inhalation delivering step comprises a breath-hold delivery period.4. A method according to claim 3, wherein the breath-hold period is atleast 10 seconds.
 5. A method according to claim 1, wherein the at leastone image is a multi-echo image.
 6. A method according to claim 5,wherein the multi-echo image is one of a slice selective and volumeselective image pattern.
 7. A method for MRI imaging the pulmonaryand/or cardiac vasculature using dissolved-phase polarized ¹²⁹Xe,comprising the steps of: delivering polarized ¹²⁹Xe gas to apredetermined region of the patient's body, the polarized gas having adissolved imaging phase associated therewith; exciting a predeterminedregion of the patient's body having a portion of the dissolved phasepolarized gas therein with at least one large flip angle RF excitationpulse; and acquiring at least one MR image associated with the dissolvedphase polarized gas after said exciting step, wherein said exciting stepis repeated within a predetermined repetition time, the predeterminedrepetition time being less than the time it takes for a given volume ofblood to move from the lungs to the heart, wherein said delivering stepcomprises inhalation of the polarized ¹²⁹Xe gas into the lungs, the¹²⁹Xe having a gas phase resonance which is higher than thedissolved-phase resonance, wherein at least a portion of the polarized¹²⁹Xe gas enters into the pulmonary vasculature in a dissolved-phase,wherein at least a portion of the dissolved-phase polarized ¹²⁹Xe thenenters the blood stream with an associated perfusion rate, and whereinthe repetition time is decreased to emphasize a signal associated withcapillaries in the pulmonary region.
 8. A method for MRI imaging thepulmonary and/or cardiac vasculature using dissolved-phase polarized¹²⁹Xe, comprising the steps of: delivering polarized ¹²⁹Xe gas to apredetermined region of the patient's body, the polarized gas having adissolved imaging phase associated therewith; exciting a predeterminedregion of the patient's body having a portion of the dissolved phasepolarized gas therein with at least one large flip angle RF excitationpulse; and acquiring at least one MR image associated with the dissolvedphase polarized gas after said exciting step, wherein said exciting stepis repeated within a predetermined repetition time, the predeterminedrepetition time being less than the time it takes for a given volume ofblood to move from the lungs to the heart, wherein said delivering stepcomprises inhalation of the polarized ¹²⁹Xe gas into the lungs, the¹²⁹Xe having a gas phase resonance which is higher than thedissolved-phase resonance, wherein at least a portion of the polarized¹²⁹Xe gas enters into the pulmonary vasculature in a dissolved-phase,wherein at least a portion of the dissolved-phase polarized ¹²⁹Xe thenenters the blood stream with an associated perfusion rate, and whereinthe repetition time is increased to include distal vasculature relativeto the pulmonary capillaries.
 9. A method for MRI imaging the pulmonaryand/or cardiac vasculature using dissolved-phase polarized 129Xe,comprising the steps of: delivering polarized ¹²⁹Xe gas to apredetermined region of the patient's body, the polarized gas having adissolved imaging phase associated therewith; exciting a predeterminedregion of the patient's body having a portion of the dissolved phasepolarized gas therein with at least one large flip angle RF excitationpulse; and acquiring at least one MR image associated with the dissolvedphase polarized gas after said exciting step, wherein said exciting stepis repeated within a predetermined repetition time, the predeterminedrepetition time being less than the time it takes for a given volume ofblood to move from the lungs to the heart, wherein dissolved-phase ¹²⁹Xehas an associated decay time constant (T1) corresponding to itspolarization life and a transverse relaxation time in blood (T₂*), andwherein for T₂* greater than about 100 ms, said acquiring step employsone of EPI and RARE multi-echo imaging methods.
 10. A method accordingto claim 8, wherein said acquiring step acquires at least 32 echoes pereach excitation pulse.
 11. A method for MRI imaging the pulmonary and/orcardiac vasculature using dissolved-phase polarized ¹²⁹Xe, comprisingthe steps of: delivering polarized ²⁹Xe gas to a predetermined region ofthe patient's body, the polarized gas having a dissolved imaging phaseassociated therewith; exciting a predetermined region of the patient'sbody having a portion of the dissolved phase polarized gas therein withat least one large flip angle RF excitation pulse; and acquiring atleast one MR image associated with the dissolved phase polarized gasafter said exciting step, wherein said exciting step is repeated withina predetermined repetition time, the predetermined repetition time beingless than the time it takes for a given volume of blood to move from thelungs to the heart, and wherein cardiac gating is used so that saidacquiring step is timed such that it is performed during slow blood flowperiods.
 12. A method for MRI imaging the pulmonary and/or cardiacvasculature using dissolved-phase polarized ¹²⁹Xe, comprising the stepsof: delivering polarized ¹²⁹Xe gas to a predetermined region of thepatient's body, the polarized gas having a dissolved imaging phaseassociated therewith; exciting a predetermined region of the patient'sbody having a portion of the dissolved phase polarized gas therein withat least one large flip angle RF excitation pulse; and acquiring atleast one MR image associated with the dissolved phase polarized gasafter said exciting step, wherein said exciting step is repeated withina predetermined repetition time, the predetermined repetition time beingless than the time it takes for a given volume of blood to move from thelungs to the heart, wherein said delivering step comprises inhalation ofthe polarized ¹²⁹Xe gas into the lungs, the ¹²⁹Xe having a gas phaseresonance which is higher than the dissolved-phase resonance, wherein atleast a portion of the polarized ¹²⁹Xe gas enters into the pulmonaryvasculature in a dissolved-phase, wherein at least a portion of thedissolved-phase polarized ¹²⁹Xe then enters the blood stream with anassociated perfusion rate, wherein the at least one image is amulti-echo image, and wherein the multi-echo imaging uses one ofgradient recalled and RF recalled echoes.
 13. A method for evaluatingthe blood flow of a patient, comprising the steps of: positioning asubject in a MR spectroscopy system capable of detecting spectroscopicsignals in a subject having a pulmonary vasculature; delivering gaseouspolarized ¹²⁹Xe to the subject; dissolving a portion of the gaseouspolarized ¹²⁹Xe into the pulmonary vasculature having an associatedblood flow path; exciting the dissolved portion of the ¹²⁹Xe with an MRspectroscopy RF excitation pulse; and evaluating blood flow of thepatient based on a spectroscopic signal corresponding to the dissolvedpolarized ¹²⁹Xe, wherein said evaluating step includes the step ofexciting the dissolved ¹²⁹Xe with a large angle RF excitation pulse,wherein the MR Spectroscopy System comprises a magnetic field operablyassociated therewith, and wherein the magnetic field strength is lessthan about 0.5 T.
 14. A method according to claim 13, wherein saidevaluating step is performed to provide real-time blood flowinformation.
 15. A method for quantitatively evaluating the blood flowrate of a subject, comprising the steps of: administering gaseouspolarized ¹²⁹Xe to a subject such that the gaseous polarized ¹²⁹Xeenters the subject's lungs; transmitting at least one large flip angleRF excitation pulse to the ¹²⁹Xe after it travels, dissolved, into thesubject's vasculature based on said administering step; obtaining afirst polarized dissolved ¹²⁹Xe spectroscopic response signal based onsaid large flip angle pulse transmitting step, the first response signalhaving a signal strength associated therewith; obtaining a secondpolarized dissolved ¹²⁹Xe spectroscopic response signal based on said atleast one large flip angle pulse transmitting step, the second responsesignal having a signal strength associated therewith, wherein saidsecond polarized dissolved ¹²⁹Xe response signal obtaining step istemporally spaced apart a time interval from said first dissolvedresponse signal obtaining step; monitoring the increase in signalstrength of the dissolved polarized ¹²⁹Xe response signal over timebased on said first and second dissolved response signal obtainingsteps; transmitting a predetermined flip angle RF excitation pulse tothe gaseous ¹²⁹Xe residing in the lung void space based on saidadministering step; obtaining a first polarized ¹²⁹Xe gas spectroscopicresponse signal based on said predetermined flip angle gaseousexcitation transmitting step; comparing the polarized ¹²⁹Xe gas responsesignal with the first and second dissolved polarized ¹²⁹Xe responsesignals; and evaluating the blood flow rate of the subject based on saidcomparing step.
 16. A method according to claim 15, further comprisingthe step of quantitatively determining the blood flow rate of thesubject based on said comparing step.
 17. A method according to claim15, further comprising obtaining a third polarized dissolved ¹²⁹Xespectroscopic response signal based on said at least one large flipangle pulse transmitting step, the third response signal having a signalstrength associated therewith, wherein said third dissolved responsesignal obtaining step is temporally spaced apart a time interval fromsaid first and second dissolved response signal obtaining steps.
 18. Amethod according to claim 16, wherein said at least one large flip angletransmitting step comprises transmitting two temporally separate largeflip angle pulses.
 19. A method according to claim 16, furthercomprising the step of calculating the slope of a line corresponding tothe dissolved ¹²⁹Xe response signal intensity over pulse repetitiontime.
 20. A method according to claim 19, further comprising the step ofmathematically dividing the slope with the value of the ¹²⁹Xe gasresponse signal generated in said gas response signal obtaining step.21. A method according to claim 16, further comprising the step ofnumerically fitting a line to the signal strength of the first andsecond dissolved ¹²⁹Xe response signals to calculate the slope of theline corresponding to the dissolved ¹²⁹Xe response signals.
 22. A methodaccording to claim 15, further comprising the step of generating aMagnetic Resonance image of the polarized ¹²⁹Xe in the lungs of thesubject subsequent to said administering step.
 23. A method according toclaim 15, further comprising the step of administering a physiologicallyactive medication to a subject and evaluating its affect on the bloodflow rate of a subject.
 24. A method according to claim 16, furthercomprising the step of determining a lung volume representative of thesubject's lungs and using the determined lung volume in saidquantitative determination step.
 25. A method according to claim 16,further comprising the step of normalizing the blood flow rate obtainedin said determining step by considering the subject's heart rate.
 26. Amethod according to claim 15, further comprising the step of evaluatingthe existence of perfusion deficiencies or abnormalities.
 27. A methodaccording to claim 26, wherein said evaluating step is carried out bymonitoring the intensity of the dissolved polarized ¹²⁹Xe responsesignal over time to obtain diagnostic information.
 28. A methodaccording to claim 27, wherein said evaluating step includes assessingcerebral perfusion.
 29. A method for quantitatively evaluating the bloodflow rate of a subject, comprising the steps of: administering gaseouspolarized ¹²⁹Xe to a subject such that the gaseous polarized ¹²⁹Xeenters the subject's lungs; transmitting at least one large flip angleRF excitation pulse to the ¹²⁹Xe after it travels, dissolved, into thesubject's vasculature based on said administering step; obtaining afirst polarized dissolved ¹²⁹Xe spectroscopic response signal based onsaid large flip angle pulse transmitting step, the first response signalhaving a signal strength associated therewith; obtaining a secondpolarized dissolved ¹²⁹Xe spectroscopic response signal based on said atleast one large flip angle pulse transmitting step, the second responsesignal having a signal strength associated therewith, wherein saidsecond dissolved polarized ¹²⁹Xe response signal obtaining step istemporally spaced apart a time interval from said first dissolvedpolarized ¹²⁹Xe response signal obtaining step; monitoring the increasein signal strength of the dissolved polarized ¹²⁹Xe response signal overtime based on said first and second dissolved response signal obtainingsteps; and evaluating the blood flow rate of the subject based on saidmonitoring step.
 30. A method according to claim 29, further comprisingthe steps of administering a medication to the subject and monitoringthe efficacy of the medication based on said evaluating blood flow ratestep.
 31. A method according to claim 29, wherein said evaluating stepcomprises the steps of: transmitting a predetermined flip angle RFexcitation pulse to the gaseous ¹²⁹Xe residing in the lung void spacebased on said administering step; obtaining a first polarized ¹²⁹Xe gasspectroscopic response signal having an associated signal strength basedon said predetermined flip angle gaseous excitation transmitting step;comparing the polarized ¹²⁹Xe gas phase response signal with the firstand second dissolved ¹²⁹Xe response signals; and quantitativelydetermining the blood flow rate of the subject based on said comparingstep.
 32. A method according to claim 29, further comprising the step ofcalculating the slope of a line corresponding to the dissolved polarized¹²⁹Xe signal intensity over pulse repetition time.
 33. A methodaccording to claim 31, further comprising the step of mathematicallydividing the slope with the value of the polarized ¹²⁹Xe gas responsesignal strength generated in said gas phase obtaining step.
 34. A methodaccording to claim 29, further comprising the step of generating aMagnetic Resonance image of the polarized ¹²⁹Xe in the lungs of thesubject subsequent to said administering step.
 35. A method according toclaim 31, further comprising the step of identifying a lung volumerepresentative of the subject's lungs and using the identified lungvolume in said blood flow rate determination step.
 36. A methodaccording to claim 31, further comprising the step of normalizing theblood flow rate obtained in said determining step by taking into accountthe subject's heart rate.
 37. A method according to claim 29, furthercomprising the step of evaluating the existence of perfusiondeficiencies or abnormalities.
 38. A method for quantitativelyevaluating perfusion abnormalities and/or the blood flow rate of asubject, comprising the steps of: administering gaseous polarized ¹²⁹Xeto a subject such that the gaseous polarized ¹²⁹Xe enters the subject'slungs; transmitting at least one large flip angle RF excitation pulse tothe ¹²⁹Xe after it travels, dissolved, into the subject's vasculaturebased on said administering step; obtaining a first polarized dissolved¹²⁹Xe spectroscopic response signal based on said large flip angle pulsetransmitting step, the first response signal having a signal strengthassociated therewith; obtaining a second polarized dissolved ¹²⁹Xespectroscopic response signal based on said at least one large flipangle pulse transmitting step, the second response signal having asignal strength associated therewith, wherein said second dissolvedpolarized ¹²⁹Xe response signal obtaining step is temporally spacedapart a time interval from said first dissolved polarized ¹²⁹Xeobtaining step; monitoring the signal strength of the dissolvedpolarized ¹²⁹Xe response signal over time based on said first and seconddissolved polarized ¹²⁹Xe response signal obtaining steps; andevaluating at least one of perfusion function or blood flow in the bloodflow path of the subject based on said monitoring step.
 39. A methodaccording to claim 38, wherein said evaluating step comprises assessingat least one of (a) perfusion deficits in the pulmonary vasculature orthe cardiac vasculature, (b) pulmonary vasculature emboli, (c) bloodflow related circulatory system deficits, and (d) restrictions andobstructions in the blood flow path of the subject.
 40. A methodaccording to claim 38, wherein said evaluating step is carried out bymonitoring the intensity of the dissolved polarized ¹²⁹Xe responsesignal over time to obtain diagnostic information.
 41. A methodaccording to claim 40, wherein said evaluating step comprises assessingcerebral perfusion.
 42. A method according to claim 40, wherein saidevaluating step comprises assessing blood flow path blockage orrestrictions.
 43. A method according to claim 38, wherein saidevaluating step comprises one or more of: (a) identifying the presenceor absence of cardiac ischemias or infarcts; (b) identifying thrombi orplaques; (c) determining therapeutic windows for administering heparin,vasodilators, antihypertensive agents, and calcium antagonists; (d)evaluating the severity or existence of ischemias; (e) evaluatingtherapies in the treatment of cerebral vasospasm; (f) assessing ischemiain large tissue masses; (g) assessing the relationship between bloodmetabolites and cerebral perfusion in cerebral ischemia for thediagnosis or treatment of Alzheimer's disease; (h) evaluating therapiesfor stroke, (i) evaluating risk factors for stroke (j) evaluatinginduced brain hypothermia on cerebral perfusion during neurosurgery forstroke (k) evaluating the effects of age on cerebral perfusion; and (l)assessing the effect of narcotics, on the ischemic brain.
 44. A methodfor MRI imaging the pulmonary and/or cardiac vasculature using polarized¹²⁹Xe dissolved in the blood stream, comprising the steps of:administering gaseous polarized ¹²⁹Xe to a subject such that the gaseouspolarized ¹²⁹Xe enters the subject's lungs; transmitting at least onelarge flip angle RF excitation pulse from an MR apparatus to a firstquantity of the ¹²⁹Xe after it travels, dissolved, into the subject'svasculature based on said administering step; substantially destroyingthe polarization of the ¹²⁹Xe dissolved in the subject's vasculaturebased on said first transmitting step; delaying a predetermined periodof time and then transmitting a second large flip angle RF excitationpulse from the MR apparatus to a second quantity of the ¹²⁹Xe after ittravels, dissolved, into the subject's vasculature, wherein thepredetermined time is sufficient to allow the uptake of the secondquantity of polarized ¹²⁹Xe into the vasculature based on saidadministering step; obtaining first and second response signals for thepolarized dissolved ¹²⁹Xe based on the corresponding first and secondtransmitting steps, the first and second response signals each having asignal strength associated therewith; transmitting a third RF excitationpulse from the MR apparatus to excite the ¹²⁹Xe gas in the lung of thesubject; obtaining a third response signal corresponding to the thirdtransmitting step; and acquiring at least one MR image comprising dataprovided by said first and second obtaining steps associated with thedissolved polarized ¹²⁹Xe in the vasculature and at least one MR imagecomprising data provided by said third obtaining step associated withthe ¹²⁹Xe in the lung, wherein the predetermined time between said firstand second transmitting steps is defined as a pulse repetition time,wherein said pulse repetition time is less than about 3 seconds, andwherein the first, second, and third obtaining steps are carried outduring a single imaging session.
 45. A method according to claim 44,wherein said at least one image is a differential MRI image comprisingdata corresponding to both the polarized ¹²⁹Xe gas in the lungs and thepolarized dissolved ¹²⁹Xe in the vasculature.
 46. A method according toclaim 44, wherein the at least one image is a multi-echo image, andwherein the multi-echo imaging uses one of gradient recalled and RFrecalled echoes.
 47. A method according to claim 44, wherein the pulserepetition time is decreased to emphasize a signal associated withcapillaries in the pulmonary region.
 48. A method according to claim 44,wherein the pulse repetition time is increased to include distalvasculature relative to the pulmonary capillaries.
 49. A methodaccording to claim 44, wherein dissolved-phase ¹²⁹Xe has an associateddecay time constant (T1) corresponding to its polarization life and atransverse relaxation time in blood (T₂*) greater than about 100 ms andsaid acquiring step employs one of EPI and RARE multi-echo imagingmethods.
 50. A method according to claim 44, wherein cardiac gating isused so that said acquiring step is timed such that it is performedduring slow blood flow periods.
 51. A method according to claim 44,wherein said method further comprising the step of providing a cardiaccoil which is positioned proximate to the cardiac region of the subject,the cardiac coil being configured to spatially limit the excitationpulses transmitted to the subject.
 52. A method according to claim 44,wherein the MR image of the dissolved polarized ¹²⁹Xe MR image and theMR image of the polarized ¹²⁹Xe gas in the lung are obtained during asingle breath-hold inhalation cycle.